The crystalline lens plays a central role in vertebrate anterior eye development and refractive vision. Loss of lens transparency, or cataract(s), is a clinically important cause of low vision that despite surgical treatment remains a leading cause (~40%) of blindness worldwide. Typically, cataract is acquired with aging (>40 yrs) as a multi-factorial or complex disorder involving environmental and genetic risk factors. In addition, cataract may be inherited as a Mendelian disorder usually with juvenile-onset, and many mouse models of human cataract have been described. While several environmental risk factors have been established for age-related cataract, little is known about the nature and precise role of genetic factors that are estimated to account for ~50% of the risk. However, there is increasing evidence that genes underlying inherited forms of cataract are also involved in age-related cataract. The overall goal of this research is to advance understanding of the molecular mechanisms/pathways that lead to cataract. Specifically, we propose to identify novel genes for inherited forms of cataract in humans, and to identify the causative gene in a mouse model of human age-related cataract using a combination of molecular genetic and genomic techniques. Results from these studies will provide new insights about the molecular basis of lens development, aging and cataractogenesis, and ultimately may contribute to the discovery of non-surgical means to delay, reverse or even prevent cataract formation. PUBLIC HEALTH RELEVANCE: Age-related cataract afflicts more than 20 million of the US population over age 40 (~17%), and despite increasing direct medical costs for surgical treatment, is the leading cause of low vision. Congenital and infantile forms of cataract are also a significant cause of visual impairment in childhood, and surgical management of pediatric cataract is susceptible to post-operative complications including, posterior capsular opacification, aphakic glaucoma or ocular hypertension, eye movement disorders (nystagmus, strabismus, amblyopia), uveitis and retinal detachment. This research aims to advance understanding of the molecular genetic mechanisms that cause cataract, and contribute to the discovery of alternative non-surgical treatments for cataract.